Scientists Discover How Prostate Gland Develops

The team behind the investigation, which was funded by the charity Yorkshire Cancer Research with further support from the EU FP7 Marie Curie ITN PRO-NEST project, says the findings could open the door to the development of new therapies for the treatment of prostate cancer. for the first time, SCIENTISTS at the University of York have discovered how the prostate gland develops according to research published today (Thursday, February 6) in Stem Cell Reports.

The Signal Pathway

Professor Norman Maitland, Director of the YCR Cancer Research Unit at the University’s Department of Biology, and colleagues have successfully outlined the underlying mechanism behind the development of the gland after studying human prostate tissue.

Vitamin A and Retinoic Acid

During the study, Dr Jayant Rane and Dr Alastair Droop discovered a ‘signalling pathway’ – a set of signals which tell proteins inside stem cells how to evolve into prostate tissue cells called basal cells and luminal cells. They found that there are 80 genes involved in this process, and the main signals responsible for the activation and regulation of this system are retinoic acid – a chemical made from vitamin A which is supplied in our diet by carrots, green vegetables and liver – and male sex hormones.

The balance of retinoic acid and male sex hormones involved in the process is highly regulated in a normal prostate gland.

The balance of retinoic acid and male sex hormones involved in the process is highly regulated in a normal prostate gland. This balance is disrupted in prostate cancer, where the level of male sex hormones is increased. This can lead to a tumour that consists mostly of luminal-like cells, with less than one stem cell in every thousand luminal cells.

Professor Maitland said: “The prostate gland is lined with specialized cells which make up the epithelium. Diseases that affect this lining are common in the prostate, but until now, very little has been known about the mechanisms which regulate prostate tissue.

“The 80 genes and the signalling mechanisms described by the team all provide potential targets for new therapies, which could be used to combat common prostate diseases, including prostate cancer. Further, comparative analysis across more than 20,000 patient samples has also shown that similar mechanisms may be used in a wide variety of human tissues.”

Professor Maitland and his team are the first to identify the role of retinoic acid in the development of prostate cells. Last year, they discovered that treatments affecting the chemical’s responses also have the potential to stop the spread of cancer.

The team at the YCR Cancer Research Unit achieved international recognition in 2005 when they became the first to identify prostate cancer stem cells, which are believed to be the ‘root cause’ of prostate cancer. Now supported by a £2.15m award from Yorkshire Cancer Research, they have since been exploring the exact molecular properties that allow these cells to spread, survive and resist aggressive treatments such as radiation and chemotherapy.

As many as 50 percent of conceptions fail and about 20 percent of clinical pregnancies end in miscarriage.

Infertility, Erectile Dysfunction and Antioxidant Connection

CORVALLIS, Ore. – A growing body of evidence suggests that antioxidants may have significant value in addressing infertility issues in both women and men. This includes erectile dysfunction, yeah!

Researchers say that large, specific clinical studies are merited to determine how much they could help.

A new analysis, published online in the journal Pharmacological Research, noted that previous studies on the potential for antioxidants to help address this serious and growing problem have been inconclusive, but that other data indicates nutritional therapies may have significant potential.

The researchers also observed that infertility problems are often an early indicator of other degenerative disease issues such as atherosclerosis, high blood pressure and congestive heart failure. The same approaches that may help treat infertility could also be of value to head off those problems, they said.

“If oxidative stress is an underlying factor causing infertility, which we think the evidence points to, we should be able to do something about it,” said Hagen, the Jamieson Chair of Healthspan Research in the Linus Pauling Institute. “This might help prevent other critical health problems as well, at an early stage when nutritional therapies often work best.”

The results from early research have been equivocal, Hagen said, but that may be because they were too small or did not focus on antioxidants. Laboratory and in-vitro studies have been very promising, especially with some newer antioxidants such as lipoic acid that have received much less attention.

“The jury is still out on this,” Hagen said. “But the problem is huge, and the data from laboratory studies is very robust, it all fits. There is evidence this might work, and the potential benefits could be enormous.”

The researchers from Oregon and Spain point, in particular, to inadequate production of nitric oxide, an agent that relaxes and dilates blood vessels. This is often caused, in turn, by free radicals that destroy nitric oxide and reduce its function. Antioxidants can help control free radicals. Some existing medical treatments for erectile dysfunction work, in part, by increasing production of nitric oxide.

Aging, which is often associated with erectile dysfunction problems, is also a time when nitric oxide synthesis begins to falter. And infertility problems in general are increasing, scientists say, as more people delay having children until older ages.

“Infertility is multifactorial and we still don’t know the precise nature of this phenomenon,” Visioli said.

If new approaches were developed successfully, the researchers said, they might help treat erectile dysfunction in men, egg implantation and endometriosis in women, and reduce the often serious and sometimes fatal condition of pre-eclampsia in pregnancy. The quality and health of semen and eggs might be improved.

As many as 50 percent of conceptions fail and about 20 percent of clinical pregnancies end in miscarriage, the researchers noted in their report. Both male and female reproductive dysfunction is believed to contribute to this high level of reproductive failure, they said, but few real causes have been identified.

“Some people and physicians are already using antioxidants to help with fertility problems, but we don’t have the real scientific evidence yet to prove its efficacy,” Hagen said. “It’s time to change that.”

Some commonly used antioxidants, such as vitamins C and E, could help, Hagen said. But others, such as lipoic acid, are a little more cutting-edge and set up a biological chain reaction that has a more sustained impact on vasomotor function and health.

Polyphenols, the phytochemicals that often give vegetables their intense color and are also found in chocolate and tea, are also of considerable interest. But many claims are being made and products marketed, the researchers said, before the appropriate science is completed – actions that have actually delayed doing the proper studies.

“There’s a large market of plant-based supplements that requires hard data,” Visioli said. “Most claims are not backed by scientific evidence and human trials. We still need to obtain proof of efficacy before people invest money and hope in preparations of doubtful efficacy.”

Schizophrenia is a chronic condition that significantly impacts the individual and the family. The disorder also has wider consequences for society in terms of significant costs to the economy. This highly prevalent condition affects approximately 1% of the worldwide population, yet there are few therapeutic options.

The predominant treatment strategy for schizophrenia is anti-psychotic medication (with or without additional talking therapy) even though this approach lacks efficacy in managing the negative symptoms of the condition, is not effective in one-third of the patient group and the side effects of the medication can be severe and debilitating.

In recent years, a number of pathophysiological processes have been identified in groups of people with schizophrenia including oxidative stress, one-carbon metabolism and immune-mediated responses. A number of studies have shown that these altered physiological mechanisms can be ameliorated by nutritional interventions in some individuals with schizophrenia.

This review published in Nutrition Journal by Megan Anne Arroll1*, Lorraine Wilder2 and James Neil2 briefly describes the aforementioned processes and outlines research that has investigated the utility of nutritional approaches as an adjunct to anti-psychotic medication which includes:

Antioxidant and vitamin B supplementation,

Neuroprotective and anti-inflammatory nutrients and

Exclusion diets as an adjunct to anti-psychotic medication

Oxidative stress and the benefits of supplementation

N-acetyl cysteine (NAC)

Alpha lipoic acid (ALA)

Melatonin (N-acetyl-5-methoxytryptamine)

Vitamins C and E

Essential polyunsaturated fatty acids (PUFAs)

L-Theanine

One carbon metabolism and B vitamins

Folate and B vitamin supplementation

Immune-mediated responses and the therapeutic benefits of casein- and gluten-free diets

Vitamin D as a risk factor for the development of schizophrenia

While none of these interventions provides a ‘one-size-fits-all’ therapeutic solution, the authors suggest that a personalized approach warrants research attention as there is growing agreement that schizophrenia is a spectrum disorder that develops from the interplay between environmental and genetic factors.

Human and rat testes respond differently to endocrine disrupting chemicals such as BPA in two thirds of all cases, according to a recent review. As human safety levels are extrapolated from rodent data, the study could lead to a re-evaluation of the acceptable daily intake for many endocrine disruptors. The review is published in a special April issue of the journal Reproduction dedicated to endocrine disruptors.

Endocrine disruptors (EDs) are compounds that interfere with animal hormone (or endocrine) systems in various ways. Sometimes, this can lead to developmental problems, including those of the reproductive system. Over the past four decades, human sperm counts have been markedly decreasing and the rate of testicular cancer rates has risen. Meanwhile, the occurance of undescended testicles and abnormally developed male urethras are also thought to be increasing. Evidence suggests that these male reproductive disorders are at least partially due to the effects of endocrine disrupting chemicals which are becoming increasingly concentrated and prevalent in the environment and that these EDs act on the testis during fetal development.

Suspected EDs include pesticides, flame retardants and chemicals found in plastic goods such as bisphenol A (BPA) – one of a group called phthalates.. Currently, the human health risk from exposure to a given endocrine disruptor is normally assessed using a rodent model. The observed safety threshold is then reduced by a factor of 100 to calculate safety levels for humans.

In a recent review, researchers from the French Institute of Health and Medical Research (INSERM), Atomic Energy Commission (CEA) and University of Paris-Diderot compared the effects of six potential EDs on the function of rat, mouse and human fetal testis at comparable stages of their development. They simulated normal testicular development in each of these species using a novel in vitro culture system called FeTA. They found that the response to these six potential EDs was similar in humans and rodents for only one third of analyses. Human testes were more than 100 times more susceptible to some compounds, including BPA, compared to in rodents. For other compounds different effects were seen between species. More recent studies have confirmed the findings using a different experimental approach.

Professor René Habert, who led the study, said: “Our work suggests that for some compounds, human and rat cells show different susceptibilities. For others, there appear to be fundamental differences in the way these compounds act in humans and rodents. We think that these differences between species are even more pronounced for reproductive functions. This means we really have to question how relevant animal data is to assessing risk in humans.”

The FeTA system is an extremely reliable system for studying testicular cell development across species. It is more efficient than in vivo methods and also avoids problems of cross-contamination. “Our work highlights the fact that we need to test the effects of potential endocrine disrupting chemicals in both rat and human cells to be able to accurately predict the risk,” said Professor Habert. “The FeTA system is a great tool for comparing effects of endocrine disruptors on testis development in different species. However, the limitation is that we cannot use it to study long-term effects, as testis development can only be maintained for up to ten days, depending on the species.”

The next stage for the research is to assess the risk of BPA substitutes, including BPS and BPF, in both human and rodents. The group is also investigating how these compounds interact with rodent and human cells at the molecular level to understand how differences between species arise. “We need to develop specific tools to study chemical toxicity in human reproductive cells; this will allow us to accurately assess safety thresholds for different compounds, and re-evaluate the acceptible daily intake levels to protect human health for some of them” said Professor Habert.

Full bibliographic informationThe review ‘Concerns about the widespread use of rodent models for human risk assessments of endocrine disruptors’ is published in a special April issue of Reproduction on Endocrine Disruptors. The review is freely accessible online: http://www.reproduction-online.org/content/147/4/R119.full

A low-fat diet in combination with supplementation with omega-3 rich fish oil may be associated with lower levels of pro-inflammatory substances and reduced cell progression scores in men with prostate cancer, research has suggested.